Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States presenting a public health burden of considerable magnitude. Chemoprevention strategies that involve pharmacological suppression of skin photocarcinogenesis have shown promise in preclinical and clinical studies, but more efficacious agents are needed. Recent research indicates that oncogene expression in premalignant and cancerous cells may represent a specific molecular vulnerability that can be targeted by personalized genetic or pharmacological intervention without impairing viability of cells that do not express the specific oncogene, a mode of conditional cytotoxicity referred to as 'synthetic-lethal'. Our recent research has identified artemisinins, an important class of redox-anti-malarials in clinical use worldwide, as synthetic- lethal anticancer agents that target disruption of cellular iron homeostasis, a common alteration of transformed cells that causes hypersensitivity to cytotoxic oxidative stress. In continuation of our current research aiming at elucidating molecular mechanisms underlying targeted inactivation of nonmelanoma and melanoma skin cancer cells by artemisinins, we propose pilot experimentation that tests the hypothesis that artemisinin-based topical intervention can suppress skin photocarcinogenesis by synthetic-lethal elimination of premalignant and malignant cutaneous keratinocytes. First, skin pharmacokinetics (cutaneous absorption profile) of artemisinin-derivatives will be established using an ex-vivo mouse skin chamber model (aim #1). Second, feasibility of artemisinin-based topical suppression of photocarcinogenesis will then be tested in the SKH-1 murine model of solar ultraviolet B-induced squamous cell carcinoma (aim #2). Critical proof-of-principle data will be generated guiding the rational design of future mechanistic and preclinical studies that validate synthetic-lethal approaches for photochemoprevention. PUBLIC HEALTH RELEVANCE: Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States creating an urgent need for more efficacious strategies antagonizing skin carcinogenesis. Our studies pursue a novel mechanism of pharmacological intervention that kills precancerous and cancerous human skin cells without causing toxic effects in normal skin cells. In this pilot project, we will first optimize skin delivery of prototpe agents (called 'artemisinins') that harness this novel molecular mechanism and then test for the first time feasibility of artemisinin-based suppression of sun light-induced skin cancer in an animal model of the disease, representing a potentially significant advance in the development of novel treatment options suppressing skin cancer.